Chronic inflammatory diseases, such as, rheumatoid arthritis (RA), are associated with premature development of cardiovascular disease (CVD). Mortality rates among US Veterans with RA are more than twice that of age-matched men in the general population, a risk that appears to be higher than that observed in other RA cohorts. Despite strong evidence that chronic inflammation accelerates CVD, currently available treatments are not sufficient to prevent the accelerated CVD. Therefore, other approaches that target the vascular effectors of chronic inflammation are needed. The long-term goal of our research program is to understand the mechanisms by which the Nox1 NADPH oxidase contributes to the pathogenesis of vascular disease and identify novel therapeutic targets to reduce CVD. In work that was funded by a VA Merit Award, we have identified mechanisms of cytokine-mediated Nox1 activation. Our findings have also established a link between epidermal growth factor receptor (EGFR) activation and Nox1 in vascular smooth muscle cell (SMC) growth and migration. In this renewal application, our objective is to integrate these findings and explore the mechanism by which chronic inflammation increases CVD. We hypothesize that chronic inflammation increases circulating EGF-like ligands, which induces vascular Nox1 expression and primes SMCs to cytokine activation, thereby promoting vascular disease. We will address the following specific aims: Aim 1: Determine the mechanism by which EGF-like ligands accelerate vascular injury via Nox1 activation. Proposed studies will be performed in cultured human vascular SMCs and assess (1) the role of Nox1 splice isoforms; (2) ROS-induced ROS mechanisms, and (3) priming effects of EGF-like ligands on SMCs? Aim 2: Determine whether interrupting EGFR-Nox1 activation in SMCs prevents accelerated development of vascular disease in chronic inflammation. Proposed studies will induce neointimal hyperplasia in genetically modified mice subjected to a model of inflammatory arthritis and examine the effects of (1) smooth muscle cell-specific deficiency of EGFR; (2) deficiency of Nox1; and (3) the inhibition of Nox1 phosphorylation, on neointimal formation. Aim 3: Determine if plasma EGF-like ligands identify RA patients at high risk for developing vascular disease. Proposed studies will utilize the Veterans Affairs Rheumatoid Arthritis (VARA) registry consisting of bio-specimens and longitudinal clinical data to investigate the association of plasma EGF-like ligands in RA patients with cardiovascular morbidity and mortality. Successful completion of these studies will provide new insights into the mechanisms by which chronic inflammation, such as RA, increases morbidity and mortality of CVD. A positive clinical impact of our proposed studies is that our findings will provide new strategies fr the development of specific targeted therapeutics for the treatment of Veterans with chronic inflammation and vascular disease.